Successful bilateral lung transplantation in pulmonary alveolar microlithiasis: A case report and review of literature

Abstract Background Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive genetic disorder with approximately 1000 known cases worldwide, in which calcium phosphate microliths deposit in the alveolar air spaces. As of writing this report, no definitive conventional therapy exists, and many PAM cases may progress to severe respiratory failure and potential death. Bilateral lung transplantation (BLx) seems to be the most optimal solution; however, this procedure is challenging along with limited reports regarding the outcome in PAM. We report a case of PAM successfully treated with BLx for the first time in Iran. Method We present the case of a 42‐year‐old female with a longstanding history of cough, not responding to conventional antitussive medication, who was diagnosed as a case of PAM following a hospitalization due to coughing, dyspnea on exertion, and hemoptysis. Despite treatment with corticosteroid and medical treatment, no improvement was achieved and she subsequently developed respiratory and right ventricular failure, with oxygen ventilation dependence. Eventually, she was scheduled for BLx. The operation was successful and during her 2‐year follow‐up, no recurrence or significant postoperative complications has been reported. Conclusion This case presentation and literature review confirm the effectiveness of BLx as a promising treatment for PAM‐diagnosed patients, improving both life expectancy and quality of life.

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease in which a mutation in the SLC34A2 gene that encodes a sodium phosphate cotransporter is responsible for decreased phosphate clearance and widespread deposition of calcium phosphate crystals, called calcospherites or microliths, within the alveolar airspaces. 1,2Currently, there is no established medical management to prevent the progression of PAM, and attempting to treat PAM empirically has been unsatisfactory; consequently, bilateral lung transplantation (BLx) remains the only definite viable treatment to change the course of the disease. 3,4Of the more than 1000 cases reported worldwide, 5 only 19 lung-transplanted patients were reported in the literature. 6No recurrence has been stated after transplantation. 7,8Herein, we described a case of severe PAM with a longstanding history, ultimately treated with a bilateral sequential lung transplant for the first time in Iran.

| Case presentation
Our patient is a 42-year-old female without any significant past medical history who underwent BLx due to PAM.Her symptoms started 8 years ago when she visited a local hospital for a persistent productive cough.There was no history of smoking or possible occupational exposure.Her parents were nonconsanguineous, and there was no family history of pulmonary disease.At that time, she received nonspecific anticough therapy (dextromethorphan and pseudoephedrine) for symptomatic relief.However, her symptoms persisted, and despite episodes of relative relief and flare-ups, she did not seek any medical attention.
She was under conservative management for 2 years until she was hospitalized in our center because of chronic cough, excessive expectoration, progressive chest tightness, and dyspnea on exertion, accompanied by hemoptysis.Physical examination revealed clubbed fingers, bilateral inspiratory crackles in the middle and lower lung fields in chest auscultation, and oxygen saturation at rest of 93%.Routine laboratory findings (cell blood counts and serum chemistries) and inflammatory markers (body core temperature, leucocyte count, and C-reactive protein) were unremarkable.A chest x-ray (CXR) showed a diffuse bilateral micronodular pattern and a "sandstorm lung" appearance (Figure 1).Highresolution computed tomography (HRCT) at the lung window demonstrated signs of apparent tiny cysts in subpleural spaces secondary to lung fibrosis, multiple calcified foci (up to 4 mm) in different parts of both lung fields, and a 10-mm granuloma in the right middle lobe.It also showed diffuse interlobular and intralobular thickening associated with ground glass opacity, suggesting a "crazy paving sign" (Figure 2).
Moreover, arterial blood gas measurements and transthoracic echocardiography (TTE) showed no clinically relevant findings.On bronchoscopy evaluation, erythema of the respiratory mucosa was the only abnormality.Bronchoalveolar lavage fluid (BALF) did not reveal respiratory pathogens and was negative for malignant cells, tuberculosis bacterial cultures, and also polymerase chain reaction (PCR) was negative for respiratory viruses, Pneumocystis jirovecii, Mycoplasma pneumonia, and Chlamydia pneumonia.Moreover, BALF microscopic analysis unveiled intra-alveolar lamellar microliths.Due to financial constraints, genomic analysis was not performed.However, we investigated her first and second-degree relatives for any instances of lung disease or related symptoms, which was unremarkable.Thus, a positive diagnosis of PAM was established based on imaging studies and biopsy results.Following the diagnosis of PAM, she was discharged with a prescription of oral prednisolone (15 mg/day) and a salbutamol inhaler (two puffs every 6 h).The treatment was tapered gradually due to lack of efficacy.
Despite medication administration, she had progressively worsening respiratory distress and hypoxia and eventually required oxygen supplement (6-8 L/min) via nasal cannula.At the six-year follow-up, she was unable to perform the 6-min walk test at baseline, with the peak of oxygen consumption within 5 m.TTE showed moderate pulmonary hypertension with pulmonary arterial systolic pressure of 50 mmHg in favor of cor pulmonale.A pulmonary function test (PFT) was suggestive of a restrictive ventilatory defect with a forced expiratory volume in 1 s (FEV1) of 1.5 L (53% of the predicted value), a forced vital capacity (FVC) of 1.55 L (47% of predicted) and an FEV1/FVC ratio of 0.96 (120% of predicted).Her second HRCT demonstrated an increased number and size of calcified foci in different parts of both lung fields and a greater extent of fibrosis compared with previous CT scans (Figure 3).
In view of worsening dyspnea and oxygen dependency, vast lung entanglement on CT, and decreased right ventricular function, she was hospitalized in our transplant center (Abu-Ali Sina charity hospital, located in Shiraz, Iran) for BLx.
The patient was placed on lung transplant waiting lists pending availability of a donor, and pulmonary rehabilitation was included in the preoperative treatment plan.On November 2021, the patient underwent BLx with size and ABO-matched donor after 5 months on the waiting list.
After general anesthesia, the procedure was performed by Clamshell incision.Once the chest was entered, the internal thoracotomy was completed posteriorly sparing the latissimus dorsi and serratus anterior muscles.The patient was connected to central extracorporeal membrane oxygenation (ECMO) after aortic and right atrium cannulas were inserted.After pneumonectomy, the implantation was conducted sequentially, starting with the most posterior anatomical structure, the bronchial anastomosis (Figure 4).At the end of the procedure, the patient was disconnected from ECMO and after the insertion of chest tubes, thoracotomy incision was closed.Total ECMO time was about six and a half hours without any major intraoperative complications.The initial medical therapy regimen consisted of methylprednisolone 1 g, tacrolimus 1 g, Cellcept 1 g, and broad-spectrum antibiotics, including vancomycin 1 g, co-trimoxazole 480 mg, piperacillin-tazobactam 4.5 mg, and amphotericin 25 mg as per lung transplant protocol.Her vital signs were stable, and she was transferred to the intensive care unit (ICU).
Cut sections of both lungs illustrated gritty-granular surfaces (Figure 5), and histological examination showed characteristic features of PAM, including diffuse filling of alveolar air spaces by lamellated calcification (Figure 6).
On the first postoperative day, she was successfully weaned off mechanical ventilation support, and nasal oxygen at a flow rate of 3 to 5 L per minute was provided.CXR was acceptable, and her TTE demonstrated acceptable right ventricle systolic pressure with SPAP of 30 mmHg.Immunosuppressive therapy was initiated with tacrolimus (2 mg twice a day), mycophenolate mofetil (1 g/day), and methylprednisolone (25 mg/day).On the fifth postoperative day, the patient presented with pneumonia symptoms, and she was treated with meropenem (1 g every 8 h) and levofloxacin (750 mg daily).She recovered uneventfully with complete remission.She was discharged from the hospital after 18 days of ICU admission with the continuation of the immunosuppressive regimen.In the first year of postoperative follow-up, the patient had relatively acceptable quality of life without any symptoms regarding the procedure, and HRCT did not show any abnormality (Figure 7).During her secondyear follow-up, the patient reported improved quality of life and no further complaints.

| DISCUSSION
PAM is an autosomal recessively inherited pulmonary disorder with a limited number of cases, and no medical therapy except transplantation has been proven as a successful and reliable treatment method. 4,5Herein, we presented the case of a 42-year-old female who went undiagnosed for 2 years despite experiencing symptoms of cough.Following confirmation of the diagnosis, she not only failed to show improvement with corticosteroid and medical treatment but also developed secondary pulmonary hypertension, progressive dyspnea, and hemoptysis.She ultimately underwent BLx and reported improved quality of life and respiratory symptoms during her 2-year follow-up.We believe that our report, among all others, could add to the body of evidence regarding the satisfactory treatment of this rare entity.
Our literature search revealed a total of 27 published cases with PAM who underwent lung transplant, which we have summarized the features of these patients in Table 1.The average age of patients diagnosed with PAM was 31.33 (SD = 5.10) years, and 51.85% were females, and that the diagnosis is usually made between the second and fourth decades of life. 5,25Previous reports have stated that family history is present in 37% to 56% of the cases, with female predominance (53.3%); however, our review demonstrated that only three (11.11%)patients had reported positive family history, and two out of three were male. 26,27Environmental factors, such as smoking and infection, play a role in accelerating the disease progression, despite the autosomal recessive inheritance pattern. 28Among these cases, four (14.81%) patients had a history of cigarette smoking.Despite our described case, her history was not significant for smoking, any occupational exposure, or any pulmonary disease in her family.The mean age at transplant for all cases was 47.26 (SD = 1.81) years, with 22 patients receiving bilateral transplant.In terms of outcome, nine patients did not exhibit any postoperative complications.Table 1 demonstrates the clinical and demographical features of lung-transplanted PAM patients based on our review of published literature up to date.
PAM is a heterogeneous disease with an extent of clinical traits from asymptomatic to significant symptoms with right-sided heart and respiratory failure. 29It has been demonstrated that while some patients have a very slow rate of disease progression, others progress rapidly. 5enerally, symptomatic patients present with dyspnea on exertion and cough, which can be accompanied by expectoration of microliths as primary complaints, and symptoms of cor pulmonale occur as a terminal manifestation similar to our case. 30Other symptoms, including chest   pain, hemoptysis, asthenia, and pneumothorax, have also been reported. 31Our patient mainly experienced chronic cough, therefore she remained undiagnosed and subsequently untreated.Physical examination is often normal, but as the disease progresses, patients may exhibit signs of digital clubbing, peripheral or central cyanosis, and bilateral fine crackles on lung auscultation. 31Furthermore, when large volumes of the lung are filled with microliths, it can result in a restrictive ventilatory function impairment with diminished perfusion capacity, as was evident in the preoperative PFT of our case. 29 peculiar aspect of PAM is clinical and radiological dissociation; generally, asymptomatic patients present with a characteristic picture of infiltrations as fine sandlike calcific micronodules, called "sandstorm lung" on chest radiographs.32 Herein, the typical "sandstorm lung" appearance was also shown on CXR.HRCT is the most useful diagnostic imaging for PAM, and its common findings include ground-glass opacities, subpleural linear calcification, confluent and diffuse calcified nodules, and dense consolidations.33 Calcifications are also visible along the bronchovascular bundles and at the central region of the bronchovascular tree.33 As the opacifications expand, mediastinal outlines become concealed and with the involvement of pleural serosa, a "white out lung" appears. 1 Moreover, the combination of groundglass attenuation and septal thickening with calcified nodules resulted in a "crazy paving" pattern that was noticeable in the presented study.34 Additionally, paraseptal and subpleural emphysema can appear as air cysts in the upper lobes, and small thin-walled subpleural cysts may illustrate the "black pleural sign," which was also evident in preoperative HRCT of our case.1,5 Although a positive diagnosis of PAM can often be established based on radiographic studies, at least another clinical feature is required to make it definite.25 A lung biopsy (transbronchial, open, or video-assisted thoracoscopic surgery) can confirm the diagnosis by identifying concentric intra-alveolar microliths in doubtable cases.35 Five out of 27 (18.51%) lug-transplanted patients were diagnosed via radiological modalities, five (18.51%) by open lung biopsy, two (7.4%) patients through transbronchial biopsy, one (3.7%)through video-assisted modalities, and genetic analysis had no place as a routine diagnostic test.At the time of the study, genetic testing was not performed in our case due to a remarkably financial burden, which is in accordance with further studies not using genetic methods.We conducted a transbronchial biopsy with virtual bronchoscopy because open lung biopsy is not feasible in all cases and is invasive.Histopathological findings show arranged microliths in concentric lamellae around an amorphous nucleus and are distinguishable from metastatic or dystrophic pulmonary calcifications.35 Moreover, a BALF analysis can occasionally reveal mild lymphocytosis and microliths but is usually inconclusive.35 In our case, the combination of transbronchial biopsy results and radiological observations confirmed the diagnosis of PAM.
To the best of our knowledge, no authorized medical or genetic treatment is currently available to slow down the progression of PAM.Treatment with systemic corticosteroids, calcium-binding agents, and bronchoalveolar whole-lung lavage have been determined to be ineffective and are used as palliative measures. 3,7In our case, prednisolone was administered prior to the diagnosis of PAM, and based on possible other differential diagnosis, however was discontinued following the ineffectiveness and ultimate pathological confirmation of PAM.While we acknowledge the theoretical possibility of prednisolone influencing the PAM course, we believe the low dose, short duration, and prompt withdrawal minimize the likelihood of significant harm. 36Although it is unclear how the efficacy of prednisolone administration was measured in a patient who was treated with prednisone prior to transplantation, but it was said to have experienced partial improvement. 3Moreover, treatment with corticosteroids has shown to suppress symptoms of cough, dyspnea, and chest tightness in some cases, and symptoms were recurred with the cessation of the treatment. 37Additionally, the potential benefits of addressing the initial differential diagnoses with prednisolone outweigh the minimal risk in this specific case.
Up to date, lung transplantation is proven to be the only beneficial treatment for end-stage cases.There is no clear recommendation about when to refer patients with PAM for lung transplant, but it should be considered prior to the onset of severe right ventricular dysfunction. 5he majority of the lung-transplanted patients were female, with the mean age of diagnosis and transplant of 22 and 47 years, respectively. 6Decisions regarding the time at which a successful transplantation should occur is when either right heart failure or severe respiratory failure with a requirement for oxygen is present, as was the case in our study. 3ecurrence after transplantation has not been observed to date during the posttransplant period. 6The most prolonged recorded survival for PAM after lung transplantation is 15 years. 13A short period of postoperative follow-up is an unfortunate limitation of our study.In terms of outcome, only one patient has been reported with symptoms of infections, and in the postoperative deceased cases after BLx, prolonged ECMO time (6 h) in combination with extensive pleural involvement has been reported to be in charge of uncontrolled hemodynamic instability and multiorgan failure. 6,16Although the optimal surgical approach ultimately depends on individual patient factors and surgeon expertise, however BLx is preferred to the unilateral because one lung replacement causes persistent shunting of blood through the native lung, subsequently filling of the alveolar spaces, and the consequent creation of large areas of intrapulmonary shunts. 38In our case, we recommended lung transplantation for the patient as a potential option for a full recovery.Improved pulmonary function, reduced oxygen requirements, and increased right ventricular ejection fraction after BLx in this study is indicative of its importance in such cases.However, further evaluation is needed to investigate patient survival and to explore risk of recurrence after lung transplantation.

| CONCLUSION
PAM is still a challenging disease due to its global rarity.Our review summarizes by far the largest number of PAM patients undergoing lung transplant.We aimed to contribute to the current understanding of this condition.Conventional therapy does not always offer benefits, and because the progression is unavoidable and the majority of patients will eventually present with respiratory and right-sided heart failure, prompt diagnosis and treatment are vital.Transplant is considerably the treatment of choice to improve both life expectancy and quality in patients with end-stage disease.Surgeons should consider the importance of performing bilateral lung transplantation in such cases regardless of the recurrence risk.

AUTHOR CONTRIBUTIONS
Parviz Mardani and Armin Amirian were the chief surgeons who performed the surgical procedures.Reyhaneh Naseri and Hadiseh Mahram collected the data and drafted the manuscript.Reyhaneh Naseri and Reza Shahriarirad revised the manuscript.Masoud Shafi, Tahmoores Niknam, and Mohammad Javad Fallahi clinically contributed to this study.All authors proofread the final version of the manuscript.

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I G U R E 2 High-resolution computed tomography of a patient with pulmonary alveolar microlithiasis.(A 1 , A 2 , A 3 ) multiple bilateral calcified micronodules diffusely scattered over the lung parenchyma through three different sections in pulmonary window setting (B 1 , B 2 , B 3 ) three different sections through the lung parenchyma showing combination of septal thickening and ground glass opacity illustrating "crazy paving sign" in the mediastinal window setting.F I G U R E 3 High-resolution computed tomography of the patient with pulmonary alveolar microlithiasis over 2 years (A 1 , A 2 ) a section of the lung in a pulmonary window setting, demonstrating expansion of fibrosis over the years (B 1 , B 2 ) a mediastinal section of the lung, showing an increased number and size of calcified foci in B 2 .

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I G U R E 4 Gross view of the left lung of the donor for a lung transplant.

F I G U R E 5
Pathologic findings in macroscopic view of the explanted lung in pulmonary alveolar microlithiasis.Cut sections of both lungs showing gritty-granular surfaces.F I G U R E 6 Gram-stained histological section of lung tissue.Arrows show diffuse alveolar air space filled by lamellated calcifications and numerous introalveolar microliths.(A) and (B) magnification at 10Â, and (C) magnification at 40Â.F I G U R E 7 High-resolution computed tomography of the patient with pulmonary alveolar microlithiasis, conducted at the first year postoperative follow-up without any abnormality.T A B L E 1 Clinical and demographical features of patients with pulmonary alveolar microlithiasis undergoing lung transplant based on a review of published literature.

1
Chest X-ray showing bilateral diffuse micronodular opacity involving all zones.